Atopic diseases, which include allergy, asthma, atopic dermatititis (or eczema) and allergic rhinitis, together constitute one of the largest group of clinical disorders requiring medical intervention. In the United Kingdom alone, atopy gives rise to 3-5 million cases and as many as 2,000 deaths each year.
Atopy is generally defined as a disorder of Immunoglobulin E (IgE) responses to common antigens, such as pollen or house dust mites. It is frequently detected by either elevated total serum IgE levels, antigen specific IgE response or positive skin tests to common allergens. In principle atopy can result from dysregulation of any part of the pathway which begins with antigen exposure and IgE response to the interaction of IgE with its receptor on mast cells, the high affinity Fc receptor Fc.sub..epsilon. RI, and the subsequent cellular activation mediated by that ligand-receptor engagement (Ravetch, Nature Genetics, 7:117-118 (1994). Cookson et al., Lancet, 333:1292-1295 (1989) have reported a genetic link between generalized atopic IgE responses and a locus on human chromosome 11q.
Fc.sub..epsilon. RI, is part of a tetrameric receptor complex consisting of an .alpha. chain, a .beta. chain and two .gamma. chains (Kinet et al., Proc. Natl. Acad. Sci. USA, 15:6483-6487 (1988)). Together, they mediate interaction with IgE-bound antigens leading to dramatic cellular responses, such as the massive degranulations of mast cells. Thought until recently to be expressed only in mast cells and basophils, the high-affinity receptor Fc.sub..epsilon. RI has been shown to be present also in Langerhans cells (Kinet, J.-P. et al., Proc. Natl. Acad. Sci. USA 85:6483-6487 (1988)), eosinophils (Sutton, B. J. and Gould, H. J., Nature (London) 366:421-428 (1993)) and peripheral monocytes (Gounni, A. S. et al., Ref 4). The .beta. subunit, Fc.sub..epsilon. RI.beta., is a 4-transmembrane protein with both the amino and carboxyl termini residing in the cytoplasm. The human CD20 antigen (Tedder, T. F., et al., Proc. Natl. Acad. Sci. USA 85:208-212 (1988)), as well as its murine equivalent Ly-44 (Tedder, T. F. et al., J. Immunol. 141:4388-4394 (1988)), are expressed only in B-cells. Functional studies with different CD20 antibodies indicate that CD20 is involved in the regulation of B-cell activation (Clark, E. A. and Lane, J. L. Annu. Rev. Immunol. 9:97-127 (1991)). The CD20 protein also contain four transmembrane domains with the amino and carboxyl ends on the same cytoplasmic side of the cell membrane. There is an overall amino acid similarity of 16% between CD20 and Fc.sub..epsilon. RI.beta.. Furthermore, the murine Fc.sub..epsilon. RI.beta. gene maps to the same region in chromosome 19 as the Ly-44 gene (Huppi, K. et al., J. Immunol. 143:3787-3791 (1989)).
The identification of genes that may play a role in IgE responses or atopic diseases would be desirable. It would also be desirable to develop an assay which can detect hereditary atopy.